1. Technical Field
This invention relates generally to permeation enhancers for agent delivery by electrotransport through a body surface. More particularly, this invention relates to a composition utilizing a permeation enhancer which is solid at temperatures encountered during manufacture and/or storage of the composition, the composition being useful in electrotransport delivery devices.
2. Background Art
In the field of drug delivery, increasing efforts have been devoted to developing devices and methods which reduce patient discomfort. Some of these efforts have focused on methods for controlled, continuous drug delivery, which provide more uniform drug concentrations to the body over time. Transdermal drug delivery offers substantial improvements over traditional delivery methods. Transdermal agent delivery, as used herein, is broadly the delivery of an agent through a body surface, such as the skin, mucosa, or nails.
One type of transdermal agent delivery is electrotransport, ie, electrically assisted transdermal delivery. "Electrotransport" refers generally to the passage of a substance through a body substrate, such as skin, mucous membranes, or nails, at least partially induced by the passage of an electrical current. For example, a therapeutic agent may be introduced into the human body by electrotransport. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport, involves the movement of a liquid through a biological membrane (eg, skin) under the influence of an electric field. Another type of electrotransport, electroporation, involves the transport of an agent through transiently-existing pores formed in a biological membrane under the influence of an electric field. In any given electrotransport process, however, more than one of these processes may be occurring simultaneously to a certain extent. Accordingly, the term "electrotransport" is used herein in its broadest possible interpretation so that it includes the electrically induced or enhanced transport of an agent, which may be charged or uncharged, or a mixture thereof, regardless of the specific mechanism(s) of transport.
A common goal in the design of transdermal drug delivery devices and the selection of delivery compositions is increasing the rate of delivery of an agent to the body. The skin functions as a primary barrier to the penetration of external substances into the body and represents a major resistance to the transdermal transport of drugs into the systemic circulation. Hence, serious efforts have been focused on reducing this resistance or enhancing the permeability of the skin to the delivery of therapeutic agents.
Various methods for increasing the rate of diffusional transdermal drug delivery have been disclosed in the art. For example, drug-impermeable backing layers, made of metal, plastic, or other materials, have been employed in skin patches in order to limit diffusion of drug away from the skin and, thereby, increase the diffusion of drug into the skin. In addition, an increased rate of absorption of an agent into the skin has been produced by adjusting the temperature and relative humidity of the adjacent atmosphere. Chemical absorption promoters or permeation enhancers have also been utilized, either as integral components of a transdermal therapeutic composition or applied to the skin prior to the therapeutic agent. For example, a composition for the passive delivery of salicylic acid, which comprises aliphatic diols, an ester of a mono- or polyhydric alcohol, and a saturated fatty acid is disclosed in WO 90/08547. Another composition containing an aliphatic 1,2-diol such as propane- or butane-diol, and a fatty oil, such as triglycerides and their fatty acid derivatives, is disclosed in WO 89/00853. In addition, U.S. Pat. Nos. 4,605,670 and 5,128,376 disclose the passive percutaneous administration of an active agent in a composition containing a mixture of
1) an ester of a C.sub.7 -C.sub.18 aliphatic acid and an alcohol, a C.sub.8 -C.sub.26 aliphatic monoalcohol or mixtures thereof, PA1 2) C.sub.4 -C.sub.6 cyclic amides such as pyrrolidones, and PA1 3) diols, triols, or mixtures thereof. PA1 R.sub.2 is H or CH.sub.3. PA1 R.sub.1 is a C.sub.4 -C.sub.18 saturated or unsaturated, cyclic or linear alkyl and preferably a C.sub.8 -C.sub.14 saturated or unsaturated, cyclic or linear alkyl; and PA1 R.sub.2 is H or CH.sub.3. PA1 R.sub.2 is H or CH.sub.3.
The latter compounds are said to increase the rate of percutaneous absorption of the agent. These passive methods, however, have generally proven of limited effectiveness in significantly increasing the amount of agent is delivered, particularly in the case of ionizable agents.
In order to overcome the limited transdermal drug fluxes inherent in passive (ie, diffusional) transdermal delivery, electrically-assisted transdermal transport of drugs has been utilized. Electrotransport devices typically require at least two electrodes, both being in electrical contact with some portion of the skin, nails, mucous membranes, or other membrane surface of the body. One electrode, commonly referred to as the "donor" or "active" electrode, is the electrode from which the agent, drug or drug precursor is delivered into the body. The other electrode, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, ie, a cation, then the anode will be the active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if the agent is negatively charged, ie, an anion, the cathode will be the donor electrode. Additionally, both the anode and cathode may be used to deliver drugs if uncharged/neutrally charged drugs are to be delivered or if both anionic and cationic drug are to be delivered. Thus, a complete electrical circuit is formed by electrical contact of the power source to the donor electrode, the donor electrode to the body, the body to the counter electrode, and the counter electrode to the power source. Furthermore, electrotransport delivery systems generally require at least one reservoir or source of the agent or drug to be delivered to the body. Examples of such agent reservoirs include a pouch or cavity, a porous sponge or pad, and a pre-formed gel body. Such agent reservoirs are electrically connected to the anode or cathode of an electrotransport device to provide a fixed or renewable source of one or more agents or drugs. In addition, electrotransport delivery systems typically have an independent electrical power source, eg, one or more batteries, and many have an electrical controller designed to regulate the flow of electric current through the electrodes and, thereby, the rate of drug delivery. The donor and counter electrodes are connected to opposite poles of the power source. Alternately, the necessary power may be supplied, at least in part, by a galvanic couple formed by the contact of two electrodes made of dissimilar materials.
Skin permeation enhancers have been utilized in transdermal electrotransport drug delivery. See for example Sanderson et al, U.S. Pat. No. 4,722,726 and Francoeur et al, U.S. Pat. No. 5,023,085. European Patent Application 93/300198.4 discloses iontophoretic transdermal delivery of agents with the aid of a broadly described group of "lipid modifiers". The modifiers are generally described as having a C.sub.5 -C.sub.28 aliphatic chain and moieties such as hemiacetals, amides, acetals, alcohols, carboxylic acids, esters, and others, but containing no more than 50-60 carbon atoms. Several dioxolanes, an aliphatic carbonate, and a pyrrolidone are exemplified.
The practical utility of electrotransport permeation enhancers is generally limited by the occurrence of adverse interactions between the enhancer and the drug, between the enhancer and the body surface, or between the enhancer and the device components. (see, "Permeation Enhancers Compatible with Transdermal Drug Delivery Systems: Part II: System Design Considerations, Pharm. Tech., pp. 54-60 (October 1990). The use of a liquid permeation enhancer in an electrotransport device intended to have a shelf-life of several months or longer can present potential problems. For example, the complexity of the manufacturing process increases when liquids must be incorporated ab initio into the delivery device. Also, some liquid organic enhancers, such as ethanol or others, may dissolve, or react with, adhesive components utilized in the assembly of the delivery device. Liquid enhancers may also reduce the shelf-life of a device as a result of interactions resulting from its being in long-term contact with the drug, with polymers present in the reservoirs, or with materials utilized in its insulating portions. Further, liquids tend to promote the corrosion of metallic components (eg, electrical components, circuit traces, the electrodes, etc) in electrotransport devices.
Therefore, there is still a need for solid permeation enhancers, especially those which may be provided in a dry, solid state, in electrotransport delivery devices.